This invention relates to a class of heteroaryl polyamines and the pharmaceutically acceptable salts thereof which are antagonists of excitatory amino acid neurotransmitters. These neurotransmitters affect neuronal cells of a variety of organisms including invertebrates and vertebrates. The polyamines of the present invention are synthetic analogs of certain polyamines found to be present in the venom of the Agelenopsis aperta spider. This invention also relates to the use of such polyamines and their salts in antagonizing excitatory amino acid neurotransmitters. These neurotransmitters affect cells such as cells in the nervous system of an organism. This invention further relates to the use of such polyamines and their salts in the treatment of excitatory amino acid neurotransmitter-mediated diseases and conditions in a mammal and in control of invertebrate pests, and to compositions comprising said polyamines and salts thereof. This invention also relates to methods of producing such polyamines.
It has been reported that the venom of the spider Agelenopsis aperta contains at least two toxins which affect calcium currents. Jackson, H., et al., Soc. Neu. Sci. Abstr. 12:1078 (1987). Those authors disclose a toxin, referred to therein as AG2, which has a molecular weight. of less than 1,000 daltons and appears to suppress calcium currents in a broad range of tissues. Further, Jackson, H. et al., Soc. Neu. Sci. Abstr. 12:730 (1986) report another toxin from Agelenopsis aperta comprising a component of about 6,000 M.W. That toxin is reported to block presynaptic transmission and it has been suggested that the toxin blocks calcium channels associated with the release of neurotransmitter.
Certain polyamines found to be present in the venom of the Agelenopsis aperta spider are disclosed in U.S. Pat. No. 5,037,846, filed Apr. 28, 1989 and assigned to the assignees hereof. Those polyamines and the pharmaceutically acceptable salts thereof are disclosed therein as blockers of excitatory amino acid receptors in cells and one such polyamine, B.sub.1 therein, is also disclosed as a blocker of calcium channels.
Compounds which are excitatory amino acid neurotransmitter antagonists have a variety of utilities. Excitatory amino acid neurotransmitter antagonists are useful in the treatment of such conditions as stroke, cerebral ischemia, neuronal degenerative disorders such as Alzheimer's disease and epilepsy and as psychotherapeutants, among others. See Excitatory Amino Acids In Health and Disease, D. Lodge, E., John Wiley and Sons Ltd., New York, NY. 1988, the teachings of which are incorporated herein by reference. Further, such compounds are useful in the study of the physiology of cells such as neuronal cells and in the control of invertebrate pests.
Glutamate is the major excitatory neurotransmitter in mammalian brain. There has been a great deal of excitement in the past decade as the developing pharmacology of glutamate receptors has suggested their differentiation into several subtypes. The glutamate receptor subtype classified by the selective action of the exogenous agonist N-methyl-Daspartate (NMDA) has been the subject of intense research since these receptors have been proposed to play a role in a variety of neurological pathologies including stroke, epilepsy, and neurodegenerative disorders such as Alzheimers's disease. There are currently two broad classes of NMDA receptor antagonists that are being aggressively pursued in search of clinically useful drugs. The first class consists of competitive antagonists which interfere with binding of glutamate to its receptor site. These compounds are characterized as highly polar compounds such as the phosphonate compounds AP7 and AP5. The highly charged structure of the competitive agents render them unable to penetrate the blood/brain barrier and limits their therapeutic utility. The second class consists of noncompetitive antagonists which block NMDA receptor function by acting at the ion channel associated with the NMDA receptor complex. These compounds include MK-801 and phencyclidine (PCP). The potential psychotomimetic effects of these classes of compounds are clear liabilities of the known drugs that work via these mechanisms.
Recently, a third class of antagonists have come under scrutiny, based on the identification of new glutamate antagonists from spider venoms. Arylamine structures isolated from the venom of Agelenopsis aperta that show potent and specific antagonism of mammalian NMDA receptors are disclosed in U.S. patent application Ser. No. 554,311, filed Jul. 17, 1990 and in U.S. Pat. No. 5,037,846, filed Jul. 31, 1990. The arylamines isolated from Agelenopsis aperta venom are composite structure built up from an aromatic acid and polyamine fragments bonded together by amide bonds. In these structures, some of the amines in the polyamine fragment are functionalized as N-hydroxy amines or quaternary ammonium salts. The chemical structures of the arylamines are distinct from the aforementioned standard competitive agents, AP5 or AP7, and the non-competitive compound MK-801. For example, polyamine AGEL 416, disclosed in aforementioned U.S. Pat. No. 5,037,846, is disclosed as having the following structure. ##STR3## The mechanism of NMDA antagonism by these arylamines is also distinct from both the competitive and MK-801/PCP classes. Thus, spider venom arylamines provide a novel class of antagonist compounds at the NMDA receptor.
Given the benefit of the disclosure herein with respect to the naturally-occurring compounds it is now possible to obtain said compounds by methods other than through isolation/purification from whole venom of Agelenopsis aperta, and correspondingly, it is also possible to synthesize analogous compounds of the same class which are not naturally-occurring.